Heavy metal salts of butenolides



United States Patent 3,472,877 HEAVY METAL SALTS OF BUTENOLIDES JosefFried, Chicago, Ill., and Eugene E. Galantay, Morristown, N.J.,assignors, by mesne assignments, to E. R- Sqnibb & Sons, Inc., New York,N.Y., a corporation of Delaware No Drawing. Original application Sept.17, 1964, Ser. No. 397,300, now Patent No. 3,326,937, dated June 20,1967. Divided and this application Feb. 20, 1967, Ser. No. 623,172

Int. Cl. C07d 103/00, 107/00; A61l 23/00 US. Cl. 260343.6 4 ClaimsABSTRACT OF THE DISCLOSURE The invention relates to heavy metal salts ofbutenolides having utility as antibacterial agents, e.g., to combatinfections caused by Staphylococcus aureus and as disinfectants andsterilizing agents.

This application is a division of application Ser. No. 397,300, filedSept. 17, 1964, now Patent 3,326,937.

This invention relates to butenolides. More particularly, the inventionrelates to the butenolieds represented by formulas III, IV and V below.

According to this invention a compound of the formula lower alkyl NCH2lower alkyl HOC (which occurs in the form of the zwitterion) or itsquaternary salt which has the formula (II) lower alkyl halogen loweralkyl-N-CH lower alkyl C is converted by reaction with a substituted orunsubstituted triphenylmethyl mercaptan to the first compound of thisinvention which has the formula IV R EC-S-CH:

HzN-C $113 o-o--o Patented Oct. 14, 1969 wherein R has the same meaningpreviously defined, which constitutes the second group of compounds ofthis invention.

The compounds of Formula IV in turn may be converted by reaction with aheavy metal salt to a metal salt complex of the formula S-(EH,

chlorine and bromine; nitrate, sulfate and lower alkanoyloxy especiallyacetate.

The conversion of the compounds of Formulas I or II to the compound ofFormula III is eifected by reaction with triphenylmethyl mercaptan or asubstituted trimethylphenyl mercaptan in an inert organic solvent suchas dimethylformamide, N,N dimethylacetamide, 1,2- dimethoxyethane(ethylene glycol dimethyl ether), 2- methoxyethyl ether(diethyleneglycol dimethyl ether), or the like, in the presence of abase such as alkali metal lower alkoxide, e.g., potassium t-butoxide,sodium ethoxide, an alkali metal hydride, e.g., sodium hydride, orsodamide, or the like, at about room temperature. The compound ofFormula III formed in this manner is then converted to the product ofFormula IV by the reaction of the triphenyl-mercaptomethyl a. tetronicacid with an ammonium salt such as ammonium acetate at a temperature inthe range of about to 200, preferably in an inert atmosphere such asnitrogen or dry ammonia.

The a amino 3 triphenylmethyl mercaptomethyl- ,5 butenolide formed as aresult of this reaction is converted into the final product of Formula Vby reaction with a metal salt such as mercuric chloride, mercuricacetate or the like, in a solvent such as 1,2 dimethoxyethane (ethyleneglycoldimethyl ether) or 2 methoxyethyl ether (diethylene glycoldimethyl ether), or the like, at ambient temperature.

The compounds of Formulas III and V are antibacterial agents useful tocombat infections caused by the organism Staphylococcus aureus,including those strains resistant to penicillin G. They may beadministered orally or parenterally in conventional pharmaceuticaldosage forms such as tablets, capsules, injectables and the like or maybe used topically in conventional vehicles such as creams, ointments andthe like. They may also be used as disinfectants or sterilizing agentsin conventional vehicles for this use. Compounds ofFormulas III and IV,in addition, serve as intermediates in the preparation of the newcompounds of Formula V.

The following examples are illustrative of the invention, alltemperatures being expressed in degrees centigrade.

EXAMPLE 1 [3-Triphenylmethylmercaptomethyl-a-tetronic acid (A) In 7 ml.of a 0.36 N solution of potassium tert.- butoxide in dimethyl'formamide(2.60 mmole's of base) there is dissolved 391.8 mg. (1.99 mmoles) offi-dimethylaminomethyl-ot-tetronic acid (switterion) and 557 mg. oftriphenylmethylmercaptan (1.99 mmoles) and allowed to react at roomtemperature under a 30 mm. vacuum for 15 hours. After addition of 0.3ml. of glacial acetic acid, the light yellow solution is evaporated(35 1. mm.) and the residue extracted with 15 ml. of ethyl acetate.

3 (B) A solution of 2.55 g. of the crude mixture obtained the procedureof Example 1, step A in methylene chloride is applied to a column of 108g. of deactivated silica gel. First, 1.09 g. of triphenylmethylmercaptan is eluted with methylene dichloride. Subsequent elution withmethylene dichloride containing ethyl acetate yields 577 mg. offl-triphenylmethylmercapto-methyl-utetronic acid which crystallizes ontrituration with carbon tetrachloride, M.P. 145-157.

EXAMPLE 2 a-Amino-fl-triphenylmethylmercaptomethyl-oafibutenolide Anintimate mixture of 1.482 g. (3.82 mmoles) ofli-trihpenylmercaptomethyl-a-tetronic acid and 0.591 g. (7.72 mmoles) ofammonium acetate is kept at 116 under nitrogen for 30 minutes. From theresulting brown oil, 1.482 g. of a gummy substance is extracted withchloroform. It is redissolved in methylene dichloride andchromatographed on a column made up from 100 g. 100/ 200 mesh Davisonsilica gel previously deactivated with 8 g. of water. Elution iscontinued with methylene dichloride. Besides triphenylmethylmercaptanand unchanged starting material, 580 mg. of the pure o't-amino-B-triphenylmethylmercaptomethyl-a,;3-butenolide is obtained whichcrystallizes on trituration with ether, M.P. 124-125 EXAMPLE 3wAmino-fi-mercaptomethyl-a,fi-butenolide mercuric chloride complex To asolution of 126.7 mg. (0.326 mmole) of a-amino-,B-triphenylmethylmercaptomethyl-a,B-butenolide in 0.17 ml. of peroxidefree 1,2-dimethoxyethane, there is added 0.46 ml. of a1,2-dimethoxyethane solution of 90 mg. (0.331 mmole) of mercuricchloride. Immediately White crystals separate, which are washed on thecentrifuge with small amounts of 1,2-dimethoxyethane to give 99.2 mg.(79.5%) of a-amino-fl-mercaptomethyl-u,fi-butenolide mercuric chloridecomplex.

EXAMPLE 4 By substituting tri(p-chlorophenyl)methyl mercaptan for thetriphenylmethyl mercaptan in Example 1 and otherwise following theprocedure in that example, [3-tri-(p-chlorophenyl)methylmercaptomethyl-a-tetronic acid is obtained.

EXAMPLE 5 By utilizing the product of Example 4 in the procedure ofExample 2,a-amino-fl-tri(p-chlorophenyl)methylmercaptomethyl-u,fi-butenolide isobtained.

EXAMPLE 6 By substituting lead (2) acetate for the mercuric chloride inthe procedure of Example 3,a-amino-p-mercaptomethyl-a,B-mercaptomethyl-a,B-butenolide lead acetatecomplex is obtained.

EXAMPLE 7 A suspension of 17 gms. of fl-dimethylaminomethyla-tetronicacid and an excess of methyl iodide in dry acetone is kept at 0 to 6'for 20 hours with occasional shaking. The acetone is removed in vacuoleaving as residue B-dimethylaminomethyl-wtetronic acid methiodide. Thisquaternary salt and a molar equivalent of tetraphenylmethylmercaptan aresuspended in dimethylformamide, then stirred and heated on an oil bath110) for one hour. Trimethyl ammonium iodide is separated by suctionfiltration and washed with methylene chloride. The washings and filtrateare combined and concentrated in vacuo at about 55. The residual browntar is taken up in a minimum volume of methylene chloride and applied toa column of deactivated silica gel to 200 mesh, 100 g. deactivated with8 gms. of water). The column is eluted continuously with methylenechloride, fractions of about 30 ml. being collected.

What is claimed is:

1. A compound of the formula s-orr; X:%C HaN-C wherein A-X is a heavymetal salt.

2. A process for the production of a compound of claim 1 which comprisesreacting a compound of the formula No references cited.

ALEX MAZEL, Primary Examiner J. M. SHAPIRO, Assistant Examiner U.S. Cl.X.R. 424-245, 279

31 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,472,877 Dated October 14, 1969 Invent0r($) Josef Fried and Euqene E.Galantay It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

[- Column 1, line 25, butenolieds" should read butenolides Column 2,line 19, "bromine; should read bromine, and in line 67, (switterion)should read (zwitterion) Column 3, line 2, after "tained" insert by andin line 15, trihpenylmercaptomethyl" should read triphenylmercaptomethylColumn 4, Claim 1, that portion of the formula reading S CH should readS CH SIGNED AND S EALED JUN 9 1970 (SEAL) Attest:

Edward M. Fletcher, In mm: E. samIYnEE, .m. Anesting Offi Commissioner01 Patent:

